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Thread: Chemo potentiates tumor resistance to chemotherapy?

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    Chemo potentiates tumor resistance to chemotherapy?

    New study out this week.

    Here's the breakdown: the drugs involved in chemotherapy used to damage rapidly-dividing cancer cells also damage healthy cells (most obviously hair follicles, which also divide rapidly). This damage induces healthy cells to increase their transcription of RNA coding for a protein called WNT16B. The protein WNT16B is a signaling molecule that is part of the Wnt signaling pathway that is known to be involved in oncogenesis (the development of cancer). The WNT16B produced by these healthy cells is then secreted into the extracellular fluid, where it affects the tumor microenvironment by activating the Wnt pathway (which promotes cell growth and survival) in nearby cancer cells, promoting their growth and chemo resistance.

    So, in brief, chemo causes healthy cells to release WNT16B, which activates the Wnt pathway in tumor cells, allowing them to survive and even develop a resistance to chemotherapy.


    Nature study (limited access): http://www.nature.com/nm/journal/vao...l/nm.2890.html


    Abstract:

    Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B

    Acquired resistance to anticancer treatments is a substantial barrier to reducing the morbidity and mortality that is attributable to malignant tumors. Components of tissue microenvironments are recognized to profoundly influence cellular phenotypes, including susceptibilities to toxic insults. Using a genome-wide analysis of transcriptional responses to genotoxic stress induced by cancer therapeutics, we identified a spectrum of secreted proteins derived from the tumor microenvironment that includes the Wnt family member wingless-type MMTV integration site family member 16B (WNT16B). We determined that WNT16B expression is regulated by nuclear factor of κ light polypeptide gene enhancer in B cells 1 (NF-κB) after DNA damage and subsequently signals in a paracrine manner to activate the canonical Wnt program in tumor cells. The expression of WNT16B in the prostate tumor microenvironment attenuated the effects of cytotoxic chemotherapy in vivo, promoting tumor cell survival and disease progression. These results delineate a mechanism by which genotoxic therapies given in a cyclical manner can enhance subsequent treatment resistance through cell nonautonomous effects that are contributed by the tumor microenvironment.

    A news article on the study: http://www.genengnews.com/gen-news-h...ance/81247144/

    Exposing the roots of chemotherapy resistance


    Scientists claim that increased production and secretion of WNT16B by fibroblasts into the tumor microenvironment plays a key role in promoting both cancer growth and acquired resistance to chemotherapy. A Fred Hutchinson Cancer Research Center-led team has shown that when stromal fibroblasts are subjected to genotoxic stress resulting from chemotherapy they upregulate by up to 64-fold the transcription of WNT16B, and this secreted factor directly impacts on tumor cell growth and chemotherapy resistance.

    Published studies by Peter S. Nelson, M.D., and colleagues demonstrated that elevation of WNT16B transcription is evident in the stroma of human prostate, breast, and ovarian cancers that have previously been treated using chemotherapy. And when the researchers looked specifically at prostate cancer patients given neoadjuvant chemotherapy, they found that higher post-therapy levels of WNT16B in the tumor microenvironment were associated with an increased likelihood of cancer recurrence.

    The tumor growth–promoting role of WNT16B produced by stromal fibroblasts subjected to genotoxic stress was demonstrated by incubating neoplastic epithelial cells in either conditioned medium from irradiated (i.e., DNA-damaged) fibroblasts that were capable of expressing and secreting WNT16B, or conditioned medium from irradiated fibroblasts that expressed a WNT16B-inhibiting shRNA. The results of this set of experiments showed that, dependent on the cell line used, cancer cells cultured in conditioned medium from the WNT16B-deficient irradiated fibroblasts were 15–35% less invasive and proliferative than those cultured in conditioned medium from unmodified irradiated fibroblasts.

    A relationship between cancer growth and WNT16B expression by stromal fibroblasts was separately demonstrated in vivo, in experimental mice implanted with prostate cancer cells and with either prostate fibroblast cells that were capable of producing WNT16B, or those that expressed a WNT16B-silencing shRNA. Tumors growing in the presence of WNT16B-expressing fibroblasts were much larger, and also more poorly differentiated and invasive than those developing in mice implanted with WNT16B-deficient fibroblasts.

    Having established that WNT16B can promote tumor growth through paracrine signaling, the researchers went on to determine that WNT16B-enriched conditioned medium from irradiated fibroblasts activated canonical Wnt signaling in different prostate cancer cell lines, resulting in the upregulation of known β-catenin target genes, and promotion of mesenchymal characteristics. β-catenin target genes were also expressed more highly in tumors with elevated stromal WNT16B expression than those with low WNT16B expression. The upregulation of WNT16B production by stromal fibroblasts exposed to genotoxic stress was induced through NF-κB binding to the WNT16B gene.

    In a final set of in vivo experiments, the Fred Hutchinson team separately demonstrated that stromal WNT16B significantly blocked the response of either breast or prostate tumors to chemotherapy.

    Dr. Nelson et al say their studies support the notion that factors released into the tumor environment by nonmalignant cells can influence cancer growth, invasiveness, and response to chemotherapy. “Our results provide strong support for previous studies that implicate constituents of the tumor microenvironment as important contributors to this resistance,” they write. And while the team says their reported data indicate that microenvironment proteins such as WNT16B represent attractive targets for boosting the effectiveness of anticancer therapies, strategies focused on inhibiting upstream master regulators, such as NF-κB, may be even more efficient and effective adjuncts to cytotoxic therapies.

    Dr. Nelson et al describe their findings in Nature Medicine, in a paper titled “Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B.”

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